Apparatus and method for promoting angiogenesis in ischemic tissue

ABSTRACT

A biologics delivery device and method of use for promoting angiogenesis in occluded vessels and ischemic tissue of a patient are provided, wherein the biologics delivery device includes a catheter having a proximal end, a distal region having a distal end, and a side wall defining a catheter lumen; an expandable member disposed in the distal region, the expandable member configured to support a subintimal space in an occluded blood vessel of a patient, and to transition between a collapsed state and an expanded state; and a hollow needle having a penetration tip deployable from inside the catheter lumen to outside the catheter lumen, and into tissue surrounding the occluded blood vessel, wherein the expandable member in the expanded state allows the flow of oxygenated blood to the occluded blood vessel. Methods of using the inventive biologics delivery device also are provided to deposit the biologic from a subintimal space to tissue surrounding the occluded blood vessel.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part application of U.S. patentapplication Ser. No. 15/072,249, filed Mar. 16, 2016, the entirecontents of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention is directed to apparatus and methods for promotingtissue perfusion in the vascular territory served by vessels occluded bysevere atherosclerosis by delivering biologics into a subintimal space,and/or by delivering biologics from the subintimal space into tissuesurrounding the vessel.

BACKGROUND OF THE INVENTION

Peripheral arterial disease (PAD) is a highly prevalent diseaseaffecting over 12 million people in the United States (Golomb et al.,Circulation, 2006). As PAD progresses, atherosclerosis and chronicinflammation can result in markedly reduced blood flow to the legs,feet, and hands. Critical limb ischemia (CLI) is the most advanced stageof PAD, and affects more than 500,000 people annually, causing rest painin the foot, non-healing ulcers, delayed wound healing, limb/digitalgangrene, and may eventually lead to amputation.

Conventional treatment for severe arterial occlusive disease includesbypassing or crossing the occlusions using endovascular techniques suchas angioplasty, atherectomy, and/or stents. However, many patients withsevere, diffuse arterial occlusive disease, as is typically seen in CLI,are either not ideal candidates for an endovascular approach topercutaneous revascularization due to their significant co-morbidities(i.e. renal dysfunction, myocardial dysfunction) or significantfunctional or nutritional debilitation. Moreover, when arterialocclusions are extensive and severely calcified, which is the typical inCLI patients with femoropopliteal and infrapopliteal occlusive disease,interventional attempts to re-establish vessel patency to improve tissueperfusion are frequency sub-optimal or unsuccessful due to inability totraverse these complex, long arterial occlusions. Given this technicalfailure to re-establish tissue perfusion, amputation is frequentlyrequired as a life saving measure, resulting in long-term disability, adiminished quality of life and substantial expenditures to the healthcare system.

In recent years, stem cell therapies have been investigated as providinga possible adjunct or alternative for patients who are either “pooroption” or “no option” candidates for a percutaneous interventionalprocedures due to extent of their occlusive disease. Stem cells arepluripotent cells with the ability to self-renew and differentiate. Thetherapeutic effect of stem cells to improve perfusion to ischemictissues was first observed when administrating bone marrow cells into amouse model of hind-limb ischemia. (Asahara et al., Circ. Res., 1999).In 2002, autologous bone marrow mononuclear cells were observed toexhibit therapeutic angiogenesis when being injected to a human patientwith ischemic limbs due to PAD. (Tateishi-Yuyama et al., Lancet, 2002).While the cellular mechanism(s) behind the therapeutic effect of stemcells is still under investigation, current studies indicate that stemcells promote neo-vascularization by angiogenesis, vasculogenesis,arteriogenesis, or a combination of the three.

Stem cells are conventionally delivered via systemic infusion (i.e.,intravenous or intra-arterial) or local injection near areas of ischemictissue. These delivery methods have remained in use, and relativelystatic, for over a decade, and may significantly hamper theeffectiveness of stem-cell therapy. Specifically, stem cell viabilityand retention rates after conventional delivery methods are extremelylow, typically less than 10% of the injected number. To compensate forthe cell loss, a much higher volume of stem cells is needed to elicit atherapeutic response. (Behfar, et al., Circ Cardiovasc Interv, 2013).However, simply injecting a larger number of stem cells cannotcompensate for inefficient delivery modalities. Furthermore, stem cellshave relatively large diameters and may occlude vessels, compromisingtheir therapeutic effect and potentially contributing to worseningischemic symptoms. (Perin et al., J Mol Cell Cardiol, 2008).

The suboptimal performance observed with conventional stem cell deliverymodalities has multiple causes. First, stem cells differ fromtraditional therapeutics in that the cells are fragile and extremelysensitive to their microenvironments. Previously known delivery methodsdeposit the stem cells directly at the occlusion sites, where—due toischemia, hypoxia, oxidative stress, or inflammation—themicroenvironment may be harsh, and contribute to massive cell apoptosis.(Kurtz, et al., Int J Stem Cells, 2008; Li, et. al. Stem Cells, 2007).Further, the cell injection process may itself contribute to poor cellviability, as injection may cause mechanical disruption to the stemcells, e.g., barotrauma caused by fluid sheer and extreme pressurefluctuations. Moreover, in certain applications, such as delivery ofstem cells to long femoropopliteal occlusions, the migration of stemcells to ischemic areas may be impeded by the long, calcifiedocclusions. Alternatively, such stem cells may be easily washed out ofthe delivery area or entrapped in organs if taken up by systemiccirculation.

In view of the foregoing drawbacks of previously known stem celldelivery methods and apparatus, there exists a need for safe andefficacious administration of biologics, such as stem cells, to occludedvessels and ischemic tissue to promote angiogenesis, especially inpatients with severely ischemic tissues. In particular, it would beadvantageous to provide methods and apparatus for delivering stem cellsto ischemic tissue that overcome previously known methods requiringmassive direct injections with low migration or uptake, or delivery ofstem cells into open arteries in the vicinity of an ischemic tissue,which results in low viability and wash out.

It therefore would be advantageous to provide methods and apparatus fordelivering stem cell therapy to patients with severely ischemic tissues,wherein such methods and apparatus enhance cell viability and retentionrates, and promote the overall therapeutic effect of stem cells.

It further would be desirable to provide apparatus and methods dedicatedto deliver stem cells and other biologics to occluded vessels of apatient in a safe and efficient manner, such that the stem cells may bedelivered to the vicinity of an occluded vessel in a protected mannerthat enhances cell viability and retention, and reduces the risk ofwash-out and entry of such cells into systemic circulation.

It also would be desirable to provide apparatus and methods to deliverstem cells such that the stem cells are delivered into a protectedenvironment with reduced mechanical disruption, thereby promoting stemcell viability.

It further would be desirable to provide apparatus and methods fordelivering biologics to promote angiogenesis in ischemic tissue thatprovides uniform distribution of the biologics along a designatedregion.

It still further would be desirable to provide apparatus and methodssuitable for delivering a metered amount of stem cells to the vicinityof an occluded vessel to promote angiogenesis.

SUMMARY OF THE INVENTION

In view of the aforementioned drawbacks of previously known stem celldelivery methods and apparatus, the present invention provides apparatusand methods for delivering biologics, such as stem cells, to asubintimal space of an occluded vessel of a patient body. In accordancewith one aspect of the invention, a subintimal space is created betweenthe medial and adventitial layers of an occluded vessel, which isexpected to provide a more hospitable, protected microenvironment forthe cells, thereby improving uptake into the surrounding ischemic tissueand reducing wash-out and the risk that such stems cells will be carriedinto systemic circulation.

Apparatus and methods are provided for delivering biologics therapiesthat advantageously are expected to reduce the amount of biologicsneeded to elicit a therapeutic response. Delivery of biologics, such asstem cells, into a supported subintimal space also is expected to reducethe potential for mechanical disruption to the biologics and improvecell viability. In addition, apparatus and methods in accordance withthe present invention are expected to provide a more uniformeddistribution of a metered amount of stem cells within a designatedregion, thereby reducing the required amount of biologics to bedeposited and reducing procedural cost.

In accordance with one aspect of the present invention, a biologicsdelivery device is provided for creating and maintaining a subintimalspace in an occluded blood vessel of a patient and for delivering abiologic into the subintimal space. The biologics delivery devicecomprises a catheter having a proximal end, a distal region having adistal end, a lumen extending there between, and a plurality ofthrough-wall apertures distributed along the distal region. Theplurality of through-wall apertures is in fluid communication with theproximal end and the lumen. The biologics delivery device preferablyfurther comprises an expandable member disposed in the distal region,which is configured to transition between a collapsed state, suitablefor insertion into the subintimal space, and an expanded state fordelivery of biologics. During delivery of biologics, the expandablemember is radially expanded to contact the walls of the subintimal spaceto support the space patent.

The biologics delivery device also may include an actuator fortransitioning the expandable member between the collapsed state and theexpanded state. The actuator also may retain the expandable member inthe expanded state during biologics delivery. The actuator may beconstructed to include a sheath configured to constrain the expandablemember in the collapsed state. In some embodiments, the actuator maycomprise a cuff disposed proximal or distal to and coupled to theexpandable member, such that the expandable member may be expanded bypushing, pulling, twisting the cuff, or a combination of such motions.

In accordance with one aspect of the present invention, the plurality ofthrough-wall apertures are radiused to reduce the risk of mechanicaldamage to the biologics during delivery. The plurality of through-wallapertures further preferably are sized to provide substantially uniformdistribution of the biologics along the distal region of the biologicsdelivery device. In some embodiments, the diameters of the plurality ofthrough-wall apertures may gradually increase in the proximal to distaldirection. In some embodiments, the plurality of through-wall aperturesare directed towards the adventitial layer.

The biologics delivery device further may comprise at least oneradiopaque marker for tracking the location of the device underfluoroscopic visualization.

A method of using the biologics delivery device for promotingangiogenesis in an ischemic area of a patient also is provided, whereinthe biologics delivery device is introduced into a previously createdsubintimal space. An expandable member disposed on the device isradially expanded to contact and support the surface of the subintimalspace. While the expandable member is retained in the expanded state tosupport the subintimal space, the biologics are substantially uniformlydistributed into the subintimal space through the plurality ofthrough-wall apertures disposed along the distal region. In addition, acontrast agent may be administered with the delivery of the biologics,so that migration of the biologics out of the subintimal space and intothe surrounding ischemic tissue may be observed under fluoroscopy.

In accordance with another aspect of the disclosure, a biologicsdelivery device is introduced into the subintimal space created betweenthe medial and adventitial layers of an occluded vessel, and isconfigured to deposit biologics from the subintimal space to tissuesurrounding the occluded vessel, such as skeletal muscle surrounding thevessels of a lower limb, thereby enhancing biologics survival andreducing the risk of systemic washout.

The biologics delivery device for delivering a biologic to tissuesurrounding an occluded blood vessel of a patient includes a catheterhaving a proximal end, a distal region having a distal end, and a sidewall defining a catheter lumen; an expandable member disposed in thedistal region, which is configured to support a subintimal space in anoccluded blood vessel of a patient, and to transition between acollapsed state and an expanded state; and a hollow needle having apenetration tip deployable from inside the catheter lumen to outside thecatheter lumen, and into the tissue. The expandable member in theexpanded state allows the flow of oxygenated blood to the occluded bloodvessel.

The biologics delivery device also may include a side opening formedthrough the side wall and disposed on the distal region, wherein thehollow needle is deployed through the side opening. The catheter lumenalso may terminate at the side opening.

The biologics delivery device further may include an actuator fortransitioning the expandable member between the collapsed state and theexpanded state. The actuator may further be configured to maintain theexpandable member in the expanded state during the delivery of thebiologic.

In accordance with another aspect of the present disclosure, the hollowneedle is configured to be advanced through the expandable member in theexpanded state. The hollow needle may be formed of nitinol. Theexpandable member may include a plurality of strands. The expandablemember may also include a mesh-like structure.

In accordance with another aspect of the present disclosure, thebiologics delivery device may include at least one radiopaque marker.

The biologic may include one or more hematopoietic stem cells,endothelial progenitor cells, mesenchymal stem cells, embryonic stemcells, induced pluripotent stem cells, growth factors, or anycombination thereof.

A method of using the biologics delivery device for promotingangiogenesis in an ischemic area of a patient also is provided, whereinthe biologics delivery device is introduced into a previously createdsubintimal space between an adventitial layer and an intimal layer of avascular wall of an occluded blood vessel, the subintimal space having asurface. The distal end of the biologics delivery device is introducedinto the subintimal space, the expandable member in the subintimal spaceis transitioned to an expanded state to contact and support the surfaceof the subintimal space. The penetration tip of the hollow needle isdeployed from inside the catheter lumen to outside the catheter lumen,and into the tissue surrounding the occluded blood vessel. A biologicthrough the biologics delivery lumen extending through the hollow needleis delivered to the tissue. In addition, a contrast agent may beadministered with the delivery of the biologics, so that migration ofthe biologics out of the subintimal space and into the surroundingischemic tissue may be observed under fluoroscopy.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B are schematic views of an illustrative biologicsdelivery device constructed in accordance with the principles of thepresent invention.

FIG. 2A is a perspective sectional view of the catheter shaft takenalong line 1-1′ of FIG. 1A.

FIG. 2B is a sectional view of the catheter shaft of FIG. 2A.

FIG. 3A is a plan view of an embodiment of the distal region of abiologics delivery device in accordance with the principles of thepresent invention, wherein the expandable member is in a collapsedstate.

FIG. 3B is a plan view of the distal region of FIG. 3A, wherein theexpandable member is in an expanded state.

FIG. 4A is a plan view of a plurality of through-wall apertures inaccordance with the principles of the present invention; while FIGS. 4Bthrough 4D are sectional views of the plurality of through-wallapertures of FIG. 4A.

FIGS. 5A and 5B illustrate the distal region of an alternativeembodiment of a biologics delivery device constructed in accordance withthe principles of the present invention.

FIGS. 6A and 6B illustrate the distal region of another alternativeembodiment of a biologics delivery device constructed in accordance withthe principles of the present invention.

FIG. 7 is a perspective view of the distal region of yet anotherembodiment of a biologics delivery device in accordance with theprinciples of the present invention.

FIGS. 8A to 8C illustrate the steps of creating a subintimal space inaccordance with the principles of the present invention.

FIG. 9 illustrates delivering biologics to the subintimal space using anembodiment of a biologics delivery device in accordance with theprinciples of the present invention.

FIGS. 10A and 10B illustrate the distal region of a biologics deliverydevice constructed in accordance with another aspect of the presentdisclosure.

FIG. 10C illustrates an alternative embodiment of a distal region of abiologics delivery device in accordance with the principles of thepresent disclosure.

FIG. 11 illustrates delivering biologics from the subintimal space totissue surrounding the occluded vessel using an embodiment of abiologics delivery device in accordance with the principles of thepresent disclosure.

DETAILED DESCRIPTION OF THE INVENTION

Arteries and veins generally are comprised of three layers: theinnermost layer called the intimal layer, the outermost layer called theadventitial layer, and the medial layer located in between the intimaland the adventitial layers. The intimal and medial layers are readilyseparated from the adventitial layer. For example, it is known that whenattempting to pass an occlusion with a guidewire, the guidewire maysometimes inadvertently penetrate the subintimal space between theintimal and the adventitial layer. Hereinafter, in the context of thisspecification, the term “intimal layer” refers to the intima/media thatadjoins the occluded vessel lumen, while the term “adventitial layer”refers to the outer layer of the vessel that may be separated from theintimal layer when a subintimal space is created.

Referring to FIGS. 1A and 1B, a biologics delivery device constructed inaccordance with the principles of the present invention is described.Biologics delivery device 100 comprises a catheter having an elongatedcatheter shaft 101 connecting proximal end 102 to distal region 107.Infusion port 103 preferably is disposed at proximal end 102 ofbiologics delivery device 100, and is in fluid communication with abiologics reservoir (not shown). The reservoir preferably comprises asyringe or pump for delivering a metered amount of biologics tobiologics delivery device 100 through infusion port 103. Distal region107 preferably comprises a plurality of through-wall apertures 110disposed along the longitudinal axis of distal region 107. Distal region107 further comprises atraumatic distal tip 104, which may include aflap or duck-bill valve to substantially prevent retrograde flow of bodyfluid, e.g., blood, through the lumen of biologics delivery device 100.Expandable member 108 is disposed over distal region 107, and isconfigured to transition between a collapsed state, suitable forinsertion into the subintimal space, and an expanded state for deliveryof biologics, with an increased diameter for contacting and supportingthe walls to define a subintimal space of a blood vessel. Expandablemember 108 may be self-expanding, wherein radially compressive force isapplied to retain expandable member 108 in the collapsed state.Alternatively, expandable member 108 may be expanded by an actuator.

Biologics delivery device 100 preferably has a length and diametersuitable for use in the desired peripheral vessel, e.g., 70 cm to 150 cmin length, with a diameter from 2.5 mm to 60 mm. Distal region 107preferably has a length of about 1 cm to 5 cm. Catheter shaft 101 may beformed of conventional materials of construction, e.g., a plasticmaterial such as polyethylene, polyvinylchloride, polyesters or thelike.

FIGS. 2A to 2B illustrate perspective and end sectional views ofbiologics delivery device 100 taken along line 1-1′ of FIG. 1A. Cathetershaft 101 comprises biologics lumen 105 and guidewire lumen 106extending along the longitudinal axis of catheter shaft 101. Biologicslumen 105 preferably has a larger diameter than guidewire lumen 106.Biologics lumen 105 is in fluid communication with infusion port 103 atthe proximal end and extends longitudinally through distal region 107,terminating at the plurality of through-wall apertures 110 of distalregion 107. Guidewire lumen 106 may extend substantially parallel tobiologics lumen 105, from proximal end 102 to distal tip 104. In someembodiments, guidewire lumen 106 may extend through an auxiliary port(not shown) disposed at proximal end 102. Catheter shaft 101 may beslidably disposed within sheath 109.

Referring to FIGS. 3A to 3B, when distal region 307 of biologicsdelivery device 300 is located in a desired subintimal location in avessel, expandable member 308 is radially expanded to support thesubintimal space during biologics delivery. Expandable member 308comprises a cage-like scaffold configured to transition between acollapsed state and an expanded state. The scaffold preferably comprisesa mesh structure comprising a plurality of mesh cells. Expandable member308 covers at least a portion of distal region 307, and further maycomprise proximal cuff 311 coupled to distal region 307 for receivingthe proximal end of the scaffold. Distal tip 304 preferably extendsdistally beyond expandable member 308 to assist in navigating through ablood vessel and the subintimal space.

As depicted in FIG. 3A, sheath 309 may be slidably disposed overexpandable member 308 to retain expandable member 308 in a collapsedstate to facilitate advancement of biologics delivery device 300 intothe subintimal space along a guidewire. The guidewire (not shown) may bea conventional guidewire that is placed under fluoroscopic guidancethrough a patent portion of a vessel and then penetrated into thesubintimal region in the vicinity of an occlusion. Biologics deliverydevice 300 may then be advanced along the guidewire to further separatethe intimal and adventitial layers of the vessel in the region of theocclusion. After distal region 307 is located in the subintimal spaceand prior to biologics delivery, sheath 309 may be retracted, allowingexpandable member 308 to resume its expanded configuration to enlargeand support the subintimal space, as shown in FIG. 3B. After thebiologic is delivered through a plurality of through-wall apertures 310,expandable member 308 may be collapsed by re-advancing sheath 309distally, thereby compressing expandable member 308 to its collapsedstate. Expandable member 308 preferably comprises a resilientbiocompatible material, such as a stainless steel or a shape-memoryalloy, such as nickel titanium.

Still referring to FIGS. 3A and 3B, biologics delivery device 300includes a plurality of through-wall apertures 310 constructed inaccordance with the principles of the present invention. Apertures 310communicate with biologics lumen 105 and may be aligned in an axialdirection along the wall of catheter shaft 101, and preferably faceoutwards toward the adventitial layer. While FIG. 3A depicts sixapertures 310 disposed in distal region 308, it should be understoodthat any number of apertures may be used. Apertures 310 may be of anysuitable shape, for example, round, elliptical, octagonal, etc.,although having a smooth circumference is generally expected to bepreferred.

Referring now to FIGS. 4A to 4D, alternative embodiment of biologicsdelivery catheter 400 constructed in accordance with the principles ofthe present invention is described. This embodiment also includes anexpandable member similar to that of the embodiment of FIGS. 3A-3B, butwhich is omitted in FIG. 4 for clarity. Biologics delivery catheter 400includes a plurality of through-wall apertures, 401 to 409, constructedin accordance with the principles of the present invention. Apertures401-409 communicate with the internal lumen of catheter 400 andpreferably are oriented outwards toward adventitia A. While FIG. 4Adepicts nine apertures 401-409 disposed in the distal region, it shouldbe understood that any number of apertures may be used. The plurality ofthrough-wall apertures 401-409 preferably gradually increase diameter orflow area in the proximal to distal direction, with the smallestapertures located nearest the proximal end of the distal region and thelargest apertures located nearest the distal end of the distal region.This graded aperture design is expected to facilitate a substantiallyuniform distribution of biologics along the length of the distal region.In accordance with a further aspect of the present invention, apertures401-409 preferably are radiused, as depicted in FIGS. 4B-4D, to avoidsharp edges that might cause mechanical damage to the biologics duringdelivery as they pass from biologics delivery lumen 410 into thesubintimal space.

As for the embodiment of FIGS. 3A-3B, apertures 401-409 may be of anysuitable shape, for example, round, elliptical, octagonal, etc.,although having a smooth circumference is generally expected to bepreferred. The apertures also may have the same or different shapes, andthe space between two adjacent apertures may be uniformed or varied toassist in uniform delivery of the biologic. As will be apparent to oneof ordinary skill based on the present disclosure, the diameters of theapertures may be determined by the size of the catheter and/or thevolume and the size of the biologics to be delivered.

Biologics lumen 410 is disposed adjacent to guidewire lumen 411 and isin fluid communication with apertures 401-409. The size and positioningof biologics lumen 410 preferably are selected to reduce biologicsresidue in the catheter shaft at the conclusion of the delivery, whichalso permits a more accurate measurement of amount of biologicsdelivered. In accordance with one aspect of the present invention, it isexpected that depositing a biologic such as stem cells within thesubintimal space will facilitate uptake into ischemic tissue, andpromote angiogenesis in the following ways: First, depositing thebiologic in the subintimal space will reduce the risk that blood flow inthe vessel will cause wash-out of the biologic and reduce the amountthat is carried into systemic circulation. Second, the subintimal spaceprovides a more protective environment for the biologic. Third, bydepositing the biologic directly into the subintimal space, uptake ofthe biologic will not be impeded by the presence of thrombus orcalcifications as would be the case if the biologic were to be depositedinto a tunnel formed with thrombus located in the vessel. Fourth,because the biologic is delivered directly into a healthier subintimaltissue environment than if delivered within the vessel proper, thebiologic is expected to be much more likely to obtain necessarynutrition from the surrounding tissue, thereby enhances survival. Fifth,because delivering the biologic into the subintimal space reduces therisk of washout, smaller amounts of biologic may be used than wouldotherwise be possible, thereby reducing the material costs of such aprocedure. Sixth, a nutrient matrix may be administered in combinationwith the biologic into the subintimal space, thereby further improvingbiologic viability.

Referring to FIGS. 5A and 5B, in accordance with another embodiment,expandable member 501 comprises a plurality of elongated strands.Proximal cuff 502 is slidably disposed on distal region 504 and engagesthe proximal ends of the plurality of strands. Distal cuff 503 isaffixed to distal region 504 and engages the distal ends of theplurality of strands. Expandable member 501 is configured to transitionbetween a collapsed state, as shown in FIG. 5A, and an expanded state,as shown in FIG. 5B. Preferably, expandable member 501 is expanded bypushing proximal cuff 502 distally, thereby causing the plurality ofstrands to expand radially outwards. Alternatively, the proximal cuffmay be affixed to the distal region, while the distal cuff is slidablydisposed on distal region, whereby pulling distal cuff 503 proximallyexpands the expandable member. Expandable member 501, in the expandedstate, may assume a substantially cylindrical shape having taperedproximal and distal ends. A clinician may actuate proximal cuff 502 ordistal cuff 503 at the proximal end of biologics delivery device 500using a wire, a suture, a sheath, or any other suitable method known inthe art.

FIGS. 6A and 6B depict another alternative embodiment of an expandablemember. Expandable member 601 comprises a plurality of helical strandsdisposed over distal region 604. Proximal cuff 602 engages the proximalends of the plurality of strands and is slidably disposed on distalregion 604, while the distal ends of the plurality helical strands areaffixed to the catheter at distal end 603. Alternatively, the pluralityof helical strands may be affixed to catheter at their proximal ends,and a cuff may be disposed to slide proximally over distal region 604 toengage the distal ends of the plurality of strands, thereby causing thehelical strands to expand radially outward. Pulling, pushing or twistingan actuator or handle disposed at the proximal end of biologics deliverydevice 600 may expand expandable member 601. The number of helicalstrands disposed over distal region 604 may range from one to six ormore, but preferably includes at least two strands 180 degrees out ofphase.

With respect to FIG. 7, a further alternative embodiment of biologicsdelivery device 700 is described, in which a distal region of biologicsdelivery device 700 comprises hollow coiled wire 701. The distal end ofhollow coiled wire 701 may be tapered to facilitate advancement invessel lumen. Hollow coiled wire 701 defines a lumen that is in fluidcommunication with a reservoir for introducing biologics into saidlumen. Hollow coiled wire 701 further comprises outwardly directedplurality of through-wall apertures for delivering biologics directedtowards the adventitia layer of a subintimal space. Consistent with theother embodiments and aspects of the present invention described above,the apertures of hollow coiled wire 701 may be of variable diameters andshapes for delivering a substantially uniformed distribution ofbiologics along the length of the coiled wire. Hollow coiled wire 701may be made of a shape-memory alloy, such as nickel titanium. Inoperation, hollow coiled wire 701 is configured to be straightened andthreaded along the longitudinal axis by guidewire 702 until disposed ina subintimal space. Hollow coiled wire 701 may then assume a coiledshape when guidewire 702 is retracted.

The distal region in accordance with the principles of the presentinvention preferably has a length of 1.0 cm to 5.0 cm and may be taperedto facilitate delivery. The expandable member may be permanently coupledto the catheter shaft or may be manufactured as a separate piece andcoupled to the device prior to use.

Referring to FIGS. 8A to 8C, a method of creating a subintimal space forbiologics delivery in accordance with the principles of the presentinvention is now described. First, as depicted in FIG. 8A, guidewire 801is advanced through vessel lumen L to a location proximate to occlusionO blocking vessel lumen L. Guidewire 801 then is advanced so that thedistal tip of the guidewire penetrates through intima I into the mediallayer of the vessel, as may be determined under fluoroscopicvisualization. With the distal tip of guidewire 801 located betweenintima I and adventitia A, guidewire 801 is further advanced distally tocreate a subintimal space there between alongside occlusion O in thevessel. Additionally, and/or alternatively, another catheter device,such as a microcatheter comprising a distal tip to facilitate piercingand/or dissection of tissue layers of the blood vessel, may be used. Ifthe additional catheter is used to enter the subintimal space, guidewire801 may be re-advanced through the additional catheter and back into thesubintimal space. The additional catheter then is withdrawn, leavingguidewire 801 positioned in the subintimal space, as shown in FIG. 8A.

The lumen defining the subintimal space may subsequently be dilatedusing a balloon angioplasty catheter, atherectomy device, by stenting,or other known techniques. As shown in FIGS. 8B and 8C, balloon catheter802 having inflatable balloon 803 at the distal end may be introducedover guidewire 801 to dilate the subintimal space. Balloon catheter 802may be advanced into the subintimal space in a delivery configuration,with balloon 803 deflated. Once the balloon is positioned in thevicinity of a desired position for biologics delivery, preferably distalto the proximal end of occlusion O, balloon 803 preferably is inflatedto expand radially to dilate the subintimal space. Balloon 803 may thenbe deflated and withdrawn over guidewire 801. Additionally and/oralternatively, subintimal laser atherectomy may be performed using alaser catheter, if significant calcification or fibrosis is present.Once the subintimal space is created and supported, balloon 803 isdeflated and balloon catheter 802 is withdrawn.

FIG. 9 depicts biologics delivery using the embodiment of biologicsdelivery device 900 similar to that described with respect to FIGS.3A-3B. Biologics delivery device 900 is advanced into the subintimalspace over guidewire 902 to a desired biologics delivery location,preferably distal to the proximal end of occlusion O. Biologics deliverydevice 900 is preferably pre-warmed to about the same temperature of thepatient, for example, 37° C.; whereas the proximal end of device 901 maybe maintained at room temperature. Expandable member 901 is introducedto the subintimal space in a collapsed state, and then is expandedradially to contact and support the walls of the subintimal space.Expandable member 901 preferably is maintained in the expanded stateduring biologics delivery, as shown in FIG. 9.

Biologics delivery device 900 may comprise one or more radiopaquemarkers to assist placement of the device under fluoroscopicvisualization, and to confirm dilation of the subintimal space prior toand during biologics delivery.

A metered amount of prepared biologics solution or suspension may beinfused into the biologics lumen from a reservoir and deposited towardsadventitia A through a plurality of through-wall apertures 903 disposedalong the distal region of biologics delivery device 900. Biologicspreferably are injected in a solution or suspension, a hydrogel, or in amicrosphere formulation that buffers the biologics during delivery andreduces mechanical damage. A fluid flow controller may be provided tometer fluid flow from the reservoir into the biologics lumen at aselected fluid pressure. The fluid or suspension used to deliver thebiologics also may include a contrast agent to assist in visualizingdelivery of the biologics into the subintimal space, and subsequentuptake into the surrounding tissue. Optionally, the biologics lumen isflushed with saline or other suitable fluid to reduce biologics residuein the biologics lumen.

The biologic may be fluorescently labeled and tracked usingscintigraphy, PET, or MRI. The expandable member preferably ismaintained in the expanded state for a predetermined period tofacilitate migration of the stem cells into the adventitial layer beforethe device is re-collapsed and withdrawn. The expandable memberpreferably is configured to re-collapse sufficiently slowly to avoiddamaging the deposited biologics.

In accordance with one aspect of the present invention, stem cells usedin conjunction with the apparatus and method described herein above maybe collected from a number of allogeneic and autologous sources.

A mixed population of various types of undifferentiated cells may becollected from a patient's bone marrow, including hematopoietic stemcells (HSCs), endothelial progenitor cells (EPCs), and mesenchymal stemcells (MSCs). HSCs are stem cells that form blood and immune cells andcan be readily isolated from bone marrow, umbilical cord blood, or aftermobilization into peripheral blood. MSCs are another type of adult bonemarrow derived stem cells with the ability to form cartilage, bone,adipose tissue, and marrow stroma, and are capable of sustainedexpression of growth factors. MSCs also may be isolated from adiposetissue, the umbilical cord, fetal liver, muscle, and lung, and can besuccessfully expanded in vitro. Endothelial progenitor cells areprimitive bone marrow cells that also are reported to possess theability to mature into cells that form vessel walls. (Luttun et al.,Trends Cardiovasc Med. 2002.) In addition to bone marrow stem cells,embryonic stem (ES) cells are capable of unlimited self-renewal whilemaintaining the potential to differentiate into almost all celllineages. The ethical issues related to ES cells promoted thedevelopment of induced pluripotent stem (iPS) cells, which share manyproperties with ES cells without the ethical concerns. Additionally, thestem cells may be combined with growth factors such as EGF, FGF, GDF,IGF, PDGF, and VEGF to promote cell differentiation.

The present disclosure also provides apparatus and methods fordelivering biologics, such as stem cells, from a subintimal space of anoccluded vessel of a patient body to tissue surrounding the occludedvessel.

In accordance with one aspect of the present disclosure, biologics maybe delivered from the subintimal space to tissue surrounding the vessel.In a non-limiting example, where the occluded vessel is located in thelower limb of a patient, tissue surrounding the occluded vessel may beskeletal muscle. Tissue surrounding the occluded arteries may receiveblood supply from other vessels, and therefore may be viable and lesshypoxic comparing to the occluded vessel. Depositing the biologics intosuch a friendlier environment is expected to enhance biologics survival,and reduce the risk of systemic washout.

Referring now to FIGS. 10A-C, alternative biologics delivery devicesconstructed in accordance with the principles of the present disclosureare described. The proximal parts of these embodiments are similar tothat of the embodiments described in FIGS. 1A, 2A, 2B, but which areomitted in FIGS. 10A-C for clarity. Distal region 1000 preferablyincludes expandable member 1001 disposed over elongated catheter shaft1005, through-wall aperture 1002 disposed on the side wall of elongatedcatheter shaft 1005, and needle 1003 configured to be retractablydeployed from lumen 1006 of elongated catheter shaft 1005, throughthrough-wall aperture 1002, to penetrate adventitial wall A, and intotissue T surrounding the occluded blood vessel. Tissue T may be anytissue surrounding the occluded blood vessel, for example, skeletalmuscle. Expandable member 1001 as shown in FIG. 10A includes a braidedstructure commonly known as the “Chinese Finger Trap.” Those skilled inthe art will understand that expandable member 1001 may comprise anyembodiments of the expandable member disclosed herein.

Still referring to FIG. 10A, needle 1003 preferably includes a biologicslumen extending therethrough. The proximal end of the biologics lumenmay be in fluid communication with a reservoir of biologics. Needle 1003preferably comprises a nitinol needle having a beveled tip, and a curveddistal region configured to be retractably deployed from the sidewall ofelongated catheter shaft 1005, forming an angle with the longitudinalaxis of elongated catheter shaft 1005. Needle 1003 may be configured todeliver biologics into tissue T. Needle 1003 has an outer diameter thatmay be fit within lumen 1006, preferably from about 20 Gauge to about 30Gauge.

Elongated catheter shaft 1005 may include additional components tofacilitate the positioning and deployment of needle 1003. As seen inFIGS. 10A-B, lumen 1006 extends through elongated catheter shaft 1005,terminating at distal tip 1007. Stop 1008 may be disposed in lumen 1006distal to through-wall aperture 1002. Alternatively, as seen in FIG.10C, lumen 1006′ may terminate at through-wall aperture 1002′, withoutextending through elongated catheter shaft 1005′ to distal tip 1007′.The distal end of needle 1003′ may be flexible and deflected by a curvedportion of elongated catheter shaft 1005′ (not shown) protruding intolumen 1006′. The curved protrusion may be an inflation balloon.

Expandable member 1001 preferably maintains in the expanded state duringdelivery of the biologics, and needle 1003 preferably extends throughthe mesh opening of expandable member 1001. In accordance with oneaspect of the present disclosure, expanding the subintimal space whiledelivering the biologics may allow for the introduction of oxygenatedblood into the vicinity of tissue T, which is expected to furtherpromote the viability of the deposited biologics.

In accordance with another aspect of the present disclosure, the beveledtip of needle 1300 may include at least one radiopaque marker.Additionally, elongated catheter shaft 1005 further may comprise atleast one radiopaque marker. The radiopaque markers may be configured totrack the location of the device, and/or deployment of needle 1003 intotissue T under fluoroscopic visualization. Additionally, and/oralternatively, the proximal end of device 1000 may include at least onefiduciary mark indicating the deployment of needle 1003.

Biologics delivery device 1000 also may include a plurality of aperturesdisposed on elongated catheter shaft 1005, and may be configured todeposit biologics into both the subintimal space and tissue Tsurrounding the occluded blood vessel.

Those skilled in the art will appreciate that the invention can bepracticed in other than the described embodiments, which are presentedfor purposes of illustration and not of limitation.

1. A biologics delivery device for delivering a biologic to tissuesurrounding an occluded blood vessel of a patient, comprising: acatheter having a proximal end, a distal region having a distal end, anda side wall defining a catheter lumen; an expandable member disposed inthe distal region, the expandable member configured to support a spacein the occluded blood vessel, and to transition between a collapsedstate and an expanded state; and a hollow needle having a penetrationtip deployable from inside the catheter lumen to outside the catheterlumen, through the expandable member, and into the tissue, wherein theexpandable member in the expanded state allows the flow of oxygenatedblood to the occluded blood vessel.
 2. The biologics delivery device ofclaim 1, further comprising a side opening formed through the side walland disposed on the distal region, wherein the hollow needle is deployedthrough the side opening.
 3. The biologics delivery device of claim 2,wherein the catheter lumen terminates at the side opening.
 4. Thebiologics delivery device of claim 1, further comprising an actuatorconfigured to transition the expandable member between the collapsedstate and the expanded state, the actuator further configured tomaintain the expandable member in the expanded state during the deliveryof the biologic.
 5. The biologics delivery device of claim 4, whereinthe actuator comprises a sheath.
 6. The biologics delivery device ofclaim 1, wherein the hollow needle is configured to be advanced throughthe expandable member in the expanded state.
 7. The biologics deliverydevice of claim 1, wherein the hollow needle is formed of nitinol. 8.The biologics delivery device of claim 1, further comprising at leastone radiopaque marker.
 9. The biologics delivery device of claim 1,wherein the expandable member comprises a plurality of strands.
 10. Thebiologics delivery device of claim 1, wherein the expandable membercomprises a mesh-like structure.
 11. The biologics delivery device ofclaim 1, wherein the biologic comprises one or more hematopoietic stemcells, endothelial progenitor cells, mesenchymal stem cells, embryonicstem cells, induced pluripotent stem cells, growth factors, or anycombination thereof. 12-20. (canceled)